Mycobacteria are a genus of aerobic intracellular bacterial organisms that, upon infection of a host, survive within endosomal compartments of monocytes and macrophages. Human mycobacterial diseases include tuberculosis (caused by M. tuberculosis), leprosy (caused by M. leprae), Bairnsdale ulcers (caused by M. ulcerans), and various infections caused by M. marinum, M. kansasii, M. scrofulaceum, M. szulgai, M. xenopi, M. fortuitum, M. chelonei, M. haemophilum and M. intracelullare (see Wolinsky, E., Chapter 37 in Microbiology: Including Immunology and Molecular Genetics, 3rd Ed., Harper & Row, Philadelphia, 1980).
One third of the world's population harbors M. tuberculosis and is at risk for developing tuberculosis (TB). In immunocompromised patients, tuberculosis is increasing at a nearly logarithmic rate, and multidrug resistant strains are appearing. In addition, Mycobacterial strains which were previously considered to be nonpathogenic strains (e.g., M. avium) have now become major killers of immunosuppressed AIDS patients. Moreover, current Mycobacterial vaccines are either inadequate (such as the BCG vaccine for M. tuberculosis) or unavailable (such as for M. leprae) (Kaufmann, S., Microbiol. Sci. 4:324-328-1987; U.S. Congress, Office of Technology Assessment, The Continuing Challenge of Tuberculosis, pp. 62-67, OTA-H-574, U.S. Government Printing Office, Washington, D.C., 1993).
Mycobacterium tuberculosis (Mtb)-specific CD4+ and CD8+ T cells are critical for the effective control of Mtb infection. In the mouse model, passive transfer of CD4+ T cells to sublethally irradiated animals renders them less susceptible to Mtb infection (Orme, J Immunol. 140:3589-3593, 1988). Mice in which the gene(s) for CD4 (CD4−/−) or for MHC Class II molecules are disrupted as well as wild-type mice depleted of CD4+ T cells demonstrate increased susceptibility to Mtb infection (Flory et al., J Leukoc Biol. 51:225-229, 1992). In humans, human immunodeficiency virus-infected individuals are exquisitely susceptible to developing tuberculosis (TB) after exposure to Mtb, supporting an essential role for CD4+ T-cells (Hirsch et al., J Infect Dis. 180:2069-2073, 1999). CD8+ T cells are also important for effective T cell immunity (see Lazarevic and Flynn, Am J Respir Crit Care Med. 166:1116-1121, 2002). In humans, Mtb-specific CD8+ T cells have been identified in Mtb-infected individuals and include CD8+ T cells that are both classically HLA-Ia restricted (see, for example, Lewinsohn et al., J Immunol. 165:925-930, 2000) and nonclassically restricted by the HLA-Ib molecules HLA-E (Lewinsohn et al., J Exp Med 187:1633-1640, 1998). However, there are no vaccines or therapeutic strategies that effectively induce an immune response, such as a CD8 response, to Mtb. Thus, a need remains for agents that can produce an immune response to Mtb that can be used for treatment and/or protection from an Mtb infection.